The mouse has proven a powerful model system for understanding the role of telomere length maintenance in cellular proliferation, including aging and cancer. Mice that completely lack telomerase activity undergo telomere shortening, which eventually leads to chromosome end-to-end fusions, genetic instability, and defects in the proliferation of certain stem cells such as the germline and hematopoietic cells. One limitation of the telomerase-deficient mouse, however, is that it does not completely mimic human stem cells, which usually possess low levels of telomerase activity despite a gradual decrease in telomere length with continued cell division. For example, mutations in the human telomerase RNA which lead to reduced but not abrogated telomerase activity lead to early bone marrow failure and an increased incidence of myeloid cancers. Therefore, it is clear that dosage effects in telomerase can play a direct role in disease, and may therefore also play a physiologic role in human aging. We have recently developed a mouse model that ideally mimics the telomere biology of humans. In mTert heterozygous embryonic stem (ES) cells and mice, telomeres continue to shorten despite the presence of telomerase activity. Although average telomere lengths become very short in mTert cells, no genetic instability is observed and a minimal amount of telomeric DNA can be detected at each chromosome end. This unique model system will allow us to assess the long-term consequences of telomere shortening in a manner that closely mimics human stem cells. For example, does the low levels of telomerase protect from, or predispose to, neoplasias in aging mice with short telomeres? We will examine the consequences of limiting telomerase function in cellular aging and genetic instability in young and old mice that are heterozygous for mTert, and in combination with deficiencies in other telomerase- or telomere-associated components. We will also employ retroviral tagging to determine the incidence of retrovirally induced cancers in older mice with limiting telomerase. To characterize novel genes whose function is important for limiting telomerase function, we have undertaken a genome-wide screen in budding yeast to identify gene deletions that exacerbate a partial loss of telomerase. Finally, we also describe the genetic and biochemical analysis of other murine telomere-associated components that are implicated, based on studies in budding yeast, to play an important role in cellular senescence and telomere integrity.